The overall UW ACE theme centers on a comprehensive developmental model of risk, risk processes, symptom emergence, and adaptation in autism spectrum disorder (ASD). According to this model, genetic risk factors influence brain development which leads to risk processes, namely altered patterns of interaction between the child and his/her environment, which further contribute to the abnormal development of neural circuitry and subsequent behavior. Project IV has two aims: (1) We seek to identify early manifestations of abnormal brain development in ASD: that is, variations in brain development that influence risk for the development of ASD. Twelve-month old infant siblings of children with autism, and comparison non-risk infants, will be studied using magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI), and relationships between brain measures and clinical course and symptom onset will be examined. Early detection of autism via biological risk markers offers the promise of presymptomatic diagnosis and, ultimately, of disease-modifying medications or behavioral intervention that can be used early in the disease process and during the presymptomatic period. (2) We plan to study children entering adolescence in order to identify brain developmental changes that may be related to onset seizure and behavioral decline during the adolescent period. We will conduct MRI and MRSI studies on a sample of 13- 14 yr old adolescents with ASD who have been previously imaged at 3-4 and 6 and 9-10 years of age, and matched comparison samples of children with developmental delay and typical development. This study will allow us to understand the relationship between variations in brain development and longer-term clinical outcome, focusing on adolescent seizure onset and cognitive decline. This project directly addresses goals outlined in the NIH Autism Research Matrix, including (1) identification of biological risk indices for the development of autism and autism-related symptoms in infants, and (2) developmental time course characterized for alterations in brain structures and connections in autism.